Alzheimer?s disease (AD) is a multifactorial, heterogeneous and enormously complex disorder characterized by progressive intellectual deterioration. Although remarkable advances have been made in unraveling the biological basis of the disease in the last two decades, that immense knowledge has not been translated in to successful therapy. With the failure of secretase inhibitors at the clinical trials, and to pursue a new strategy, we reasoned that by increasing soluble APP? (sAPP?), a powerful neurotrophic factor derived from APP, it may be possible to reverse AD. Therefore, we developed a novel assay to quantify sAPP? based on AlphaLISA technology, synthesized new 575 thiazole derivatives, and screened them for their effect on sAPP?. Out of several hits, we focused on one compound, THPI-244 that robustly increased sAPP? levels in the primary screen. We validated the role of THPI-244 in increasing sAPP? in the secondary and tertiary assays. We confirmed that THPI-244 can increase sAPP? levels at as low as 50 nM in NT2 cells, human primary neurons and fibroblasts derived from AD patients. THPI-244 did not alter the activities of secretases. Importantly, THPI-244 increased sAPP? independent of protein kinase C (PKC). The active compound THPI- 244 was found to have significant toxicity only above 40 ?M, thus giving a therapeutic window of 800. Interestingly, THPI-244 robustly increased neurite outgrowth and dendritic arbor in human primary neurons, suggesting that increased sAPP? may be responsible. Most importantly, THPI-244 passes through the blood brain barrier. Our goal in this proposal is first to validate in vivo safety and pharmacokinetics/dynamics (PK/PD) of THPI-244 and its analogs through ADMET characterization. We will also make more THPI-244 analogs and identify compounds by SAR and medicinal chemistry optimization with better brain penetration and bioavailability to increase more sAPP? levels. Second, we want to confirm in vivo efficacy in increasing sAPP? levels, and whether THPI-244 also reduces A?, amyloid plaques and prevent learning and memory deficits in a mouse model of AD. Further, we will quantify THPI-244/analog concentrations in the brain by LC-MS for correlative comparisons between sAPP? levels, plaque burden and compound levels. It is an innovative promising approach to test a compound that robustly increases a powerful neurotrophic factor sAPP?, which also significantly reduces A? levels with enormous therapeutic implications for AD.